Re: Hong Kong - 225G mutation found
2009-11-23
Hong Kong reports 225G in Fully Recovered 1 Year Old Male from July at Prince of Wales Hospital
225G is
not new.
The public perception of
225G and the media linkage to
hemorrhagic pneumonia is new.
These
Hydra Effect viral backgrounds carrying
225G within
ΣPF11 are, in fact,
very dangerous strains for what they are doing now and, more importantly, for
where they are going . . . no question exists about that risk tendency. The only question is why hasn't the science community driven the clinical linkages to the forefront before this week?
Fatal outcomes have been documented on record since
July in multiple cases from Brasil.
Prince of Wales Hospital in Hong Kong, notable for their handling of the
SARS epidemic and additional limited waves in the following years, has
released data today concerning the very popular polymorphism,
225G. A one year old male child
presented on July 25 and was reported to have exhibited symptoms as early as July 22. The report indicates a discharge 3 days after admittance with recovery.
One week of illness. One important discussion point for those characterising
225G as essentially a high morbidity polymorphism.
We certainly
do not impeach the idea of higher morbidity.
Biasing any induction solely on singular reports like this Hong Kong case is errant logic, but the evidence does suggest that
patience and some exertion may be required to accurately surmise the effector mechanisms of
PF11 with and without the pairing of
206T and
225G. Proceeding with a data basis will slowly build the well-supported pyramidal steps required to undertake a capstone solution against this genetically simple, yet clinically complex disease.
We expect to see another
half dozen of the major research areas also report
225G, not because the change is new, but because they’ve had the reins lightened, the leash lengthened, on this particular revision and are now encouraged to report this popular news item. This polymorphism,
225G, is seeded around the world.
225G is not as wide or as deeply penetrating as
225E. Our team expected and predicted this
Hydra Effect with
multiple, human-fit strains on
diverse genetic backgrounds that would
co-circulate in an emerging pandemic due to
Influenza Flux during the pre-
PF11<sub>Ω</sub> phases. An enterprising question might be, “How many
Hydra strains will
co-circulate in each phase?”
Numerous sub-species are spreading according to the genetic databases, including
TamiFlu Resistant and
epitope variant strains. The lead US public health agency reports again this week an instance of a
low reactor against the antisera. Additionally,
silent spread may be expected due to the
wide geography of consistent SNP genetics. The present stock explanation of spontaneous random "mutation" will soon be replaced with more rigourous descriptions based on patterns found in factual data.
The epidemiology of this virus did not suddenly change, just the
perception. The only thing that has changed in the last few days is that the leading public health agencies have allowed public reporting of the
225G revision. This particular popular
225G with commensurate background of
206T has been in active circulation
since May after emerging in April,
vectored from both New York and Georgia, and is on record with
documented fatal cases since July.
Nothing new there.
Why are the offical public health agencies raising awareness only now? While we do
applaud the release of information and the present focus on matching clinicals to the sequences, we also caution against
obverse speculation. A primary topic of concern is
Cytokinic Dysregulation. Reliance on inspecific terms like "
Cytokine Storm" in the media will only continue to misinform the public on a process that is far less understood than the lead investigators would like to admit.
All of which returns us to the basic categories:
- What we do know?
- What we don't know?
What we do know?
Now that matched clinical data is available, however limited, a
potential correlation is being drawn on lung tropism. The standing bench studies, including the
Palese and JKT team collaboration in 2006, detailing
variant tropism based on
differential HA reception at
α2-3 and α2-6-linked sialic acids evaluated correlative to protein 225 lend evidence to the concept of deep lung involvement though the experiments were conducted by varying permutations of proteins 190 and 225 on
1918 variants. Whereas, we stand in 2009 with quite different genetics that
require cross-validation prior to citation with applicability to
PF11.
Tissue type targets are compelling studies and this particular superarray protocol may prove even more useful on
PF11 than
1918 samples. We note that though
1918 and
PF11 now share
190D and
225G, that all
1918 public sequences show
206S.
206T continues to emerge and conserve regionally in
PF11. All
225G bearing strains after April show
206T, except the July
CatNS1706 and the undated
Vladivostok01.
Reproducing the glycan microarray procedure with the contemporary and ideal dataset including
Brasil and
Catalonia may bring a tigher focus onto today's issues. We couldn't ask for a more balanced set of
control factors with Catalonia offering sequences less than one week apart demonstrating both important pairings:
206S/225G and
206T/225G . . . a bench review made to order.
We also do know that a proper immune response, that is a
timely and regulated innate immune response, is not occurring in certain of these patients. When the
n +1 generations of the virus progeny begin to
lyse the host cells, that
failure of innate immune function to have responded
early leads to an
undetected and massive viral load due to the
rapid replication trait of
PF11. The cell detritus and the density of moving viral particles elicit a
host-driven,
limited “self-destruct” series of events because the multiple levels of early detection parameters have been bypassed
leaving the core essentially defenseless.
What we don’t know?
Though
Cytokinic Dysregulation is occurring in most cases at some level of interchange, the
225G and
225E strains may potentially interfere at a more profound level with the early innate response by
amplifying the
PF11 conserved effect of the
NS1 paired Glutamates at aa96 & 97 that
suppresses the IFN synthesis instantiation cycle. Influenza bench researchers don’t know exactly where the failure is occurring or at which combination of cell-to-cell signalers in
PF11 or the
PF11 225G strains. Until those identification studies are designed, undertaken and reproduced, discussion at this point is stark hypothesis based frequently on the
speaker’s sheer lack of present research content mastery. Apparently, saying “
I don’t know?” and then returning to the bench to design and gather a proper foundation of data is a skill rarely encouraged in our “Science for Hire” era.
Our team is unimpressed that the wider science community, with such broad analytical skills and exceptional equipment, relies on
pseudo-explanation, this cloud of diversion, by invoking the “
Cytokine Storm” phrase. More than 20 well-characterised and 100 identified distinct molecular signal functions are at work in the early immune response,
including cytokines,
but not limited to that class of communicators. Tagging a term for PR purposes is much simpler than tagging a molecule for tracking, but you received your instruments because you can think, not for your ability to improvise inventive talk.
Think.
Eighty billion dollars in research should arrive at a better answer with
higher specificity and actionability than the blanket “
Cytokine Storm” tome. Data and procedure discover Facts. Anything less is
purely Public Relations.
Our team continues to hold an opinion that we first described in 2006 concerning
Cytokinic Dysregulation and the
NS1 protein of Influenza. Succinctly, the viral ability to suspend innate immunity for up to two days post-infection, as
characterised by Mount Sinai this year, prevents the early and
required pro-inflammatory Cytokinic Response to viral detection. That blunting, taken in conjunction with detailed studies around adaptive immunity, may result not only in failure to clear the virus from some patients in a timely fashion, but also in failure to produce a
useful quantity and competence of memory T-cells and Ab. The early failure to clear a
rapidly replicating virus like
H5N1 or
PF11 results in a frank trauma to the immune system when the
first generations of viral progeny lyse their host cells after being undetected and
flood the tissues with virii and toxic cell detritus. That
disorderly surge of
human and viral proteins
en masse activates a
late and
cascading pro-inflammatory response that frequently fails to down-regulate properly.
This explanation is contrary to "pop" science reports that a
normal and robust immune response over-generates cytokines and attacks self indiscriminately. We hold that, by the time the virus has lysed thousands of cells and released millions of virii, that most
adjacent tissue areas are "fair game" for immune response due to toxic cell detritus and viral travel. That
flooding of antigen and waste matter,
widespread and instantaneous to the immune system, may further interact with some virally induced derangement of the
alternative pathway of complement and generate the intensive up-regulation of signaling, pro-inflammation cascades and the resultant tissue damage described in the clinicals as DIC, DAH and ARDS.
Ergo, the findings of massive tissue damage on necropsy is the result of a
failed early innate immune response, not a
normal robust response. A normal, properly up- and down-regulated robust innate response clears infection in more than 90% of various infections (viral, fungal and bacterial) and proceeds to generate Ab in short order via the adaptive arm of immunity.
When viral hosting cells properly detect intrusion, flag themselves for
apoptosis (cell death) and are then assisted by cytotoxic T-cells, the injection of
fragmentins via
perforin "tubes" induces an endogenous apoptotic program literally cutting DNA into 200 base multimers (fragments) and eventually condensing
chromatin. That
organised molecular result is far less inflammatory and far more useful for antigen identification than the
disorderly outcome of a virally "
exploded" cell. Now you can see why
proper genetic expression during each phase of this programmed cell death guarantees a
lower pathology than the
chaotic and toxic outcome of
lytic host cell destruction resulting from viral
NS1-induced,
delayed genetic expression.
A confluence of
PF11 traits (failed early detection, multi-tropism and rapid replication) against the host-pathogen interface may force a limited
"self-destruct" in the host upon eventual detection in an attempt to save the organism. That limited "
self-destruct" is not the desired outcome of a normal and robust immune response, but occurs due to a failure of the immune system to detect and respond
early in the process.
Timing matters.
Individual viral genetics and individual host immune genetic expression are
primary effectors that must no longer be discounted under the clouds of some nebulous "
Cytokine Storm" or Mysterious Mutation.
May we see the sequences paired with the clinicals?
